There is a marked sex difference in the activity of the hepatic enzymes which catalyze the sulfation of several toxic bile salts, in particular, lithocholate, a bacterial product of chenodeoxycholate. The latter bile salt is being used in the medical dissolution of cholesterol gallstones in man. The sex difference in activity is mediated through differing amounts of three bile salt sulfotransferases, separable by DEAE-cellulose ion exchange chromatography. This proposal is directed at determining the relationship between the individual bile sulfotransferases, at a chemical and enzymatic level and will address the issue the issue of which hormones, directly or indirectly, affect the sex difference in activity at the level of the individual bile salt sulfotransferases. It has been suggested that the sex difference in activity is under the control of the steroid sex hormones, estradiol and testosterone. However, it is more likely that the pituitary hormones play an important role in the regulation of sulfotransferase activity. Preliminary data has indicated that the hypoinsulinemia of diabetes leads to deregulation of the sex difference, possibly through a marked reduction of prolactin release. Specifically, a model based on a prolactin-estrogen receptor-estrogen control system will be tested using hormone (estradiol-prolactin) administration in normal, castrated, castrated/adrenalectomized, hypophysectomized and diabetic rats. In addition to measurement of individual bile salt sulfotransferases, the serum concentrations of estradiol, testosterone and the pituitary hormones (LH, FSH and prolactin) will be determined in each model. Both hepatic cytoplasmic and nuclear estrogen receptors will be measured in order to assess the validity of the model.